Myeloablative Hematopoietic Stem Cell Transplantation with a Non-total Body Irradiation Regimen for Treating Pediatric Acute Lymphoblastic Leukemia

소아 급성림프모구백혈병에서의 비전신방사선조사 조혈모세포이식

임영태

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¹

¹

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²

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1

영남대학교 의과대학 소아과학교실,

대구파티마병원 소아청소년과

Myeloablative Hematopoietic Stem Cell Transplantation with a Non-total Body Irradiation Regimen for Treating Pediatric Acute Lymphoblastic Leukemia

Young Tae Lim, M.D.

, Kyu Ho Lee, M.D.

, Saeyoon Kim, M.D., Ph.D.

, Sun Young Park, M.D.

, Jeong Ok Hah, M.D., Ph.D.

and Jae Min Lee, M.D.

1

Department of Pediatrics, College of Medicine, Yeungnam University,

2

Department of Pediatrics, Daegu Fatima Hospital, Daegu, Korea

Background: Total body irradiation (TBI) has been traditionally used as a conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) in patients with pediatric leukemia. However, TBI can cause late sequelae such as growth impairment, cataract, hormone abnormalities, infertility, neurocognitive effects, and secondary malignancy in pediatric patients.

Methods: This single center retrospective study included 22 patients with acute lympho- blastic leukemia who were aged ＜18 years and underwent HSCT between May 1999 and December 2014; seven patients received a TBI-based regimen and 15 received a non-TBI regimen.

Results: The overall survival and event-free survival rates in the TBI group were not significantly different from those in the non-TBI group (overall survival rate 71% vs. 73%, respectively; P=0.906; event-free survival rate 71% vs. 73%, respectively P=0.923).

Conclusion: Our results indicate that non-TBI conditioning regimens can be an alter- native treatment option of the treatment of pediatric acute lymphoblastic leukemia under- going HSCT.

pISSN 2233-5250 / eISSN 2233-4580 https://doi.org/10.15264/cpho.2017.24.1.55 Clin Pediatr Hematol Oncol 2017;24:55∼63

Received on March 15, 2017 Revised on March 31, 2017 Accepted on April 19, 2017

Corresponding Author: Jae Min Lee Department of Pediatrics, Yeungnam University Hospital, 170, Hyeonchung-ro, Nam-gu, Daegu 42415, Korea

Tel: +82-53-620-3530 Fax: +82-53-629-2252 E-mail: mopic@yu.ac.kr

ORCID ID: orcid.org/0000-0001-6822-1051

Key Words: Hematopoietic stem cell transplantation, Total body irradiation, Acute lym- phoblastic leukemia, Children

Introduction

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, constituting one-third of all pediatric cancers, and is the most frequent cause of cancer-related death in patients aged less than 20 years. Because of recent

advancements in ALL therapy, the overall survival (OS) rate

of patients with ALL has increased from ＜10% in the 1960s

to over 90% at present [1]. Treatment of pediatric ALL varies

depending on clinical features such as the biologic features

of leukemia cells and response to treatment. Combined

chemotherapy is used for treatment of patients with stand-

ard risk, whereas hematopoietic stem cell transplantation

(HSCT) is performed in case of relapse or high-risk patients, including those with t(4;11)(q21;q23), t(9;22)(q34;q11.2), hypodiploidy, and hyperleukocytosis [2,3].

Since its introduction about 50 years ago, HSCT has been established as an important therapeutic modality for various diseases such as hematological malignancies, and diseases related to bone marrow failure and immunodeficiency [4].

An HSCT course mainly consists of a conditioning phase followed by stem cell infusion. The conditioning phase re- moves cancer cells and simultaneously induces immuno- suppression for successful engraftment of stem cells. A myeloablative conditioning regimen, which consists of total body irradiation (TBI) and cyclophosphamide, is commonly used as a conditioning method for HSCT in pediatric ALL [5]. TBI has unique advantages over chemotherapy, such as a therapeutic effect on sanctuary sites such as the testes and central nervous system, a homogenous dose regardless of blood supply, and no extrication- or detoxifica- tion-associated challenges [6]. However, TBI can cause vari- ous adverse effects such as growth impairment, cataract, hormone abnormalities, infertility, neurocognitive effects, and secondary malignancy in pediatric patients [7-10]. Therefore, non-TBI-based conditioning methods have been developed;

conditioning regimens combining busulfan and other an- ti-tumor agents are commonly used as representative non-TBI-based regimens. Busulfan-based regimens do not induce the adverse effects associated with TBI-based regi- mens, but have a higher rate of relapse after transplantation than TBI-based conditioning regimens do[11]. In addition, busulfan-based regimens have a weak anti-tumor effect on sanctuary sites, including the testes, compared to TBI-based regimens. For pediatric patients with ALL, a conditioning regimen should be carefully selected after considering the advantages and disadvantages of TBI.

Results of previous studies have indicated that TBI-based conditioning regimens are superior to non-TBI-based con- ditioning regimens in terms of therapeutic outcome [5,12].

However, most of these studies were performed in patient populations that included both adults and children with various kinds of cancers. Therefore, in this study, we retro- spectively compared survival outcomes and late complica- tions between a TBI group and non-TBI group.

 Materials and Methods

1) Patient eligibility

This retrospective study was conducted in 22 pediatric

patients with ALL who were aged ＜18 years and who un-

derwent HSCT at the Department of Pediatrics of

Yeungnam University Medical Center in Daegu, South

Korea between May 1999 and December 2014. The follow-

ing parameters were retrospectively compared between the

two groups and included in our analysis: age at trans-

plantation, time from diagnosis to transplantation, white

blood cell (WBC) count at transplantation, patient sex, dis-

ease status, donor status, stem cell source, time of neu-

trophil engraftment, time of platelet engraftment, frequen-

cies of acute graft-versus-host disease (GVHD) and chronic

GVHD, overall survival (OS), event free survival (EFS), re-

lapse after transplantation, and death. OS was defined as

the period from stem cell injection to death or last fol-

low-up observation, whereas EFS was defined as survival

with no event, i.e., relapse or death. The patients were div-

ided into a TBI and a non-TBI group: in the TBI group,

cyclophosphamide and melphalan were used as condition-

ing regimens with TBI, whereas, in the non-TBI group, bu-

sulfan was used as the primary agent in conjunction with

other agents such as melphalan, fludarabine, and cyclo-

phosphamide. The best available source of stem cells was

selected from among bone marrow, peripheral blood, and

umbilical cord blood. Regarding donor status, a related

full-matched donor was considered the top priority; if un-

available, an unrelated donor or mismatched donor was al-

so considered. If no donor was available, autologous stem

cell transplantation was considered. Cyclosporin and me-

thotrexate were mainly used for GVHD prophylaxis, and

anti-thymocyte globulin was added in cases with an un-

related donor. Neutrophil engraftment time was defined as

the number of days required after transplantation to achieve

an absolute neutrophil count of at least 0.5×10

cells/L,

and platelet engraftment time was defined as the number

of days required to achieve a platelet count of at least

20.0×10

cells/L without platelet transfusion. For GVHD,

acute GVHD was graded by degree of invasion into skin,

Table 1. Patient characteristics

Total n (%) TBI group n (%) Non-TBI group n (%)

P-value

Number of patients 22 7 15

Median age at diagnosis (years) (range) 5.9 (0.4-15.8) 8.2 (2.9-15.8) 3.8 (0.4-13.1) 0.098

Age 1-10 14 (63.6) 4 (57) 10 (66.7)

Age ＜1 and ＞10 8 (36.4) 3 (43) 5 (33.3)

WBC count at diagnosis (range) 35,705 (1,140-836,000) 5,800 (3,400-774000) 50,100 (1,140-836,000) 0.503

＜50,000 12 (55) 5 (71) 7 (47)

＞50,000 10 (45) 2 (29) 8 (53)

Risk groups 0.356

Standard risk 8 (36) 3 (43) 5 (33)

High risk 14 (64) 4 (57) 10 (67)

Median age at transplant (years) (range) 8.4 (0.9-17.6) 9.6 (6.7-17.6) 6.6 (0.9-14.8) 0.072 Time from diagnosis to transplant (years) 1.4 (0.5-6.4) 2.4 (0.8-4.9) 1.4 (0.5-6.4) 0.572

Sex 0.083

Male 13 (59) 6 (86) 7 (47)

Female 9 (41) 1 (14) 8 (53)

Disease status 0.029

CR1 7 (32) 0 (0) 7 (47)

CR2 15 (68) 7 (100) 8 (53)

Immunophenotype 0.724

B 17 (77.3) 6 (85.7) 11 (73.3)

T 4 (18.2) 1 (14.3) 3 (20)

Biphenotype 1 (4.5) 0 (0) 1 (6.7)

Donor status 0.103

Related full match 5 (22.7) 4 (57.1) 1 (6.7)

Related mismatch 3 (13.6) 0 (0) 3 (20)

Unrelated full match 6 (27.3) 1 (14.3) 5 (33.3)

Unrelated mismatch 5 (22.7) 1 (14.3) 4 (26.7)

Auto 3 (13.6) 1 (14.3) 2 (13.3)

Stem cell source 0.061

Bone marrow 5 (22.7) 4 (57.1) 1 (6.7)

Peripheral blood 8 (36.4) 2 (28.6) 6 (40)

Cord blood 8 (36.4) 1 (14.3) 7 (46.7)

Bone marrow+cord blood 1 (4.5) 0 (0) 1 (6.7)

TNC×10⁸/kg, median (range) 5.6 (0.6-19.9) 2.6 (1.9-5.7) 8.2 (0.6-20.0) CD34＋×10⁶/kg, median (range) 3.2 (0.2-12.4) 1.1 (0.4-3.6) 3.4 (0.2-12.4)

Neutrophil engraftment (days) 15 (10-27) 18 (11-26) 14 (10-27) 0.803

Platelet engraftment (days) 40 (11-180) 39 (33-102) 47 (11-180) 0.792

Relapse after transplant 0.311

No 21 (95.5) 7 (100) 14 (93.3)

Yes 1 (4.5) 0 (0) 1 (6.7)

Death after transplant 0.655

No 16 (72.7) 5 (71.4) 11 (73.3)

Yes 6 (27.3) 2 (28.6) 4 (26.7)

Acute GVHD (Grade 2-Grade 4) 9 (40.9) 4 (57.1) 5 (33.3)

Chronic GVHD 0.783

Limited 6 (27.3) 2 (28.6) 4 (26.7)

Extensive 1 (4.5) 0 (0) 1 (6.7)

CR, complete remission; GVHD, graft-versus-host disease; TBI, total body irradiation; TNC, total neutrophil count; WBC, white blood cell.

Table 2. Conditioning regimens

Number of patients Total body irradiation

Total body irradiation/cyclophosphamide 1 Total body irradiation/melphalan 1 Total body irradiation/cyclophosphamide/

melphalan

5 Non-total body irradiation

Busulfan/melphalan/fludarabine 6 Busulfan/melphalan/cyclophosphamide 6

Busulfan/melphalan 1

Busulfan/fludarabine 1

Busulfan/cyclophosphamide 1

liver, or gastrointestinal and other organs [13], whereas chronic GVHD was classified as limited or extensive in- vasion [14].

The study protocol was also approved by the Institutional Review Board of Yeungnam University Hospital. 

2) Statistical analysis

Mean values were compared using the Mann–Whitney test. OS and EFS were analyzed using Kaplan–Meier curve analysis. P-values ＜0.05 were considered statistically signi- ficant. Analyses were conducted using IBM SPSS Statistics 23.0 software (SPSS Inc., Chicago, IL, USA).

Results

A significant difference in disease status at the time of HSCT was observed between the two groups (Table 1). All patients in the TBI group underwent HSCT at CR2, whereas of the 15 patients in the non-TBI group, seven underwent HSCT at CR1 and eight underwent HSCT at CR2. Among the seven patients in the non-TBI group who underwent HSCT at CR1, MLL gene rearrangement was detected in three patients; induction failure, and T cell lineage were de- tected in one patient each; one patient was aged less than 12 months at the time of HSCT; and positive minimal re- sidual disease was consistently confirmed in one patient af- ter chemotherapy (TEL-AML1 PCR positive).

Among the seven patients in the TBI group, five showed successful neutrophil and platelet engraftment; one girl died due to sepsis 4 days after HSCT whereas one boy showed successful neutrophil engraftment 11 days after HSCT, but expired because of the occurrence of sepsis before platelet engraftment. Among the 15 patients in the non-TBI group, 12 showed successful neutrophil and platelet engraftment.

Among the remaining three patients, one expired because of acute GVHD after transplantation, whereas two showed successful neutrophil engraftment after transplantation but failed to achieve platelet engraftment; one of them died be- cause of Pneumocystis jirovecii pneumonia whereas the other died because of relapse after transplantation. Condi- tioning regimens used for the patients in the two treatment groups are described in Table 2.

Transplant characteristics of patients are provided in Table 3. Among the 22 patients, relapse occurred in one patient in the non-TBI group. He was BCR-ABL-positive and experienced a relapse in the bone marrow after trans- plantation (patient #3).

Death occurred in six of the 22 patients: two in the TBI group and four in the non-TBI group. Among the two pa- tients in the TBI group, one girl (patient #22) expired be- cause of sepsis on day 4 after HSCT whereas one boy (patient #18) died because of sepsis, despite successful neutrophil engraftment but platelet engraftment failure after transplantation. Among the four patients in the non-TBI group who died, one girl (patient #9) died because of P.

jirovecii pneumonia after transplantation, two boys (patient

#8, #12) died because of severe acute GVHD, and the other boy (patient #3) died after relapse.

The 5-year OS rate in the TBI group was not significantly different from that in the non-TBI group (Fig. 1A). The 5-year EFS rate in the TBI group was not significantly differ- ent from that in the non-TBI group (Fig. 1B). In analyzing only CR2 patients, the 5-year OS and EFS did not show sig- nificant differences between the TBI group and the Non-TBI group (Fig. 2A, B).

Regarding late complications, two of the seven patients

in the TBI group died during therapy. Among the remain-

ing five patients, three had short stature whereas two had

testicular hypogonadism. In addition, Type 1 diabetes mel-

litus occurred in one patient 17 months after transplan-

tation. No endocrine complications such as short stature or

Ta ble 3. Tran sp la nt ch ar acter isti cs of N on-TB I p at ie nt s Pat ie nt No Sex Age at di ag nos is (year s)

A ge at HS CT (year s)

D iseas e stat us at H SCT Im m un o- ph en otype C yt ogeneti cs D on or H LA m atch Stem cel l so urce C ond iti oning regi m en Th e r easo n for HS CT

Relap se after HS C T

Out co m e (year s

) 1 F 2. 1 2. 8 C R1 B t(4 ;1 1)(q 21 ;q 23 );M LL M U D Fu ll mat ch PB Bu- M el -F lu M LL rear ran gem en t N o NE D ( 0. 7) 2 M 12 .4 13 .3 CR 1 T N orm al kar yo typ e M RD Full m at ch BM Bu -M el- C y T- A LL N o N ED (2.3) 3 M 3. 3 4. 8 C R2 B t(9; 12 )(q3 4; q11 .2 );B CR -A BL 1 M M RD 2 M M PB Bu -Flu BC R-AB L1 Yes D eat h ( 0. 9) 4 M 13. 1 14. 3 C R1 B t(12 ;2 1) (p 13; q2 2) ;T E L- A M L1 M U D Full m at ch PB Bu -M el- Fl u Po si tive M RD s N o N ED (2.5) 5 M 1. 4 5. 8 CR 2 B M LL rearr angem ent M M U RD 2 M M PB Bu -C y C R2 N o N ED (1.9) 6 F 1. 7 5. 7 C R2 B t(12 ;2 1) (p 13; q2 2) ;T E L- A M L1 MMR D 2 MM BM ＋ C B Bu -M el -F lu M RD N o N ED ( 3. 0) 7 F 0. 7 1. 6 C R1 B t(4 ;1 1)(q 21 ;q 23 );M LL M U D Fu ll mat ch C B Bu- M el -F lu M LL rear ran gem en t N o NE D ( 6. 0) 8 M 6. 0 8. 7 C R2 B t(9; 12 )(q3 4; q11 .2 ); BC R- ABL 1 M M RD 1 M M C B Bu -M el -F lu BC R- A BL 1 N o D ea th , (0 .4 ) 9 F 1.8 3.1 C R2 T de l(6 q) M M U RD 2 M M C B Bu -M el -F lu T-A LL N o D ea th (0 .2 ) 10 F 11 .9 13 .5 C R2 B N orm al kar yo typ e A uto Full m at ch PB Bu -M el- C y C R2 N o N ED (6.7) 11 M 8. 4 14 .8 CR 2 B N orm al kar yo typ e A uto Full m at ch PB Bu -M el- C y C R2 N o N ED (7.8) 12 M 5. 8 6. 6 C R1 T de l(9 q) M U D Fu ll mat ch C B Bu- M el -Cy T- AL L N o D ea th ( 0. 1) 13 F 3. 8 9. 4 C R2 Bi phe not ype N or m al k ar yot ype M M U RD 2 M M CB Bu- M el -C y C R2 N o NE D ( 10. 7) 14 F 0. 4 0. 9 C R1 B H yperdiploidy M M U RD 1 M M C B Bu -M el Infan t A LL N o N ED (9.4) 15 F 6. 6 7. 4 C R1 B 11 q23 r ear ra nge m en t M U D Fu ll mat ch C B Bu- M el -Cy M LL rear ran gem en t N o NE D ( 9. 7) 16 M 2. 9 6. 7 C R2 B N or mal k ar yot ype M RD Fu ll mat ch BM TBI -M el -C y C R2 N o NE D ( 10. 0) 17 M 6. 2 8. 6 C R2 T N or mal k ar yot ype M M U RD 2 M M CB TBI -M el -C y C R2 N o NE D ( 10. 3) 18 M 15. 8 16. 6 C R2 B N or mal k ar yot yp e M UD Fu ll mat ch PB TBI -C y C R2 N o De at h ( 0. 5) 19 M 8. 2 9. 6 C R2 B N or mal k ar yot ype M RD Fu ll mat ch BM TBI -M el -C y C R2 N o NE D ( 13. 1) 20 M 11. 7 12. 6 C R2 B T( 4; 11) (q21 ;q 23) M RD Fu ll mat ch BM TBI -M el CR2 N o N ED ( 13. 0) 21 M 5. 0 8. 1 C R2 B N or mal k ar yot ype M RD Fu ll mat ch BM TBI -M el -C y C R2 N o NE D ( 13. 2) 22 F 12. 8 17. 6 C R2 B 45, XX ,t( 9; 22) (q34 ; q1 1. 2) , - 15 A uto Full m at ch PB TB I-M el -C y C R2 N o D ea th (0 .0 1) N ED, n o ev ide nc e of di se as e; M RD, m at che d r el at ed do nor ; M UD, m at che d un re la te d don or ; M M RD, mi sm at ch ed r el at ed don or ; M M U RD, m ism at ch ed un re lated d on or ; M RD s, m in im al r esidu al disease; M M , m ism at ch ; PB , p er ip her al bloo d; BM , bo ne m ar row ; CB , cord b lo od ; B u, bu sulf an; Flu, flu dar abi ne ; C y, cy cl op hos ph ami de ; M el , m elp ha la n; T BI , to ta l b od y i rra dia tio n.

Su rv iv al tim e fro m H SC T.

Fig. 2. Overall survival (A) and event-free survival (B) after a total body irradiation-based conditioning regimen (n=7) compared with

Fig. 1. Overall survival (A) and event-free survival (B) after a total body irradiation-based conditioning regimen (n=7) compared with

hypogonadism were observed in the patients in the non-TBI group. No secondary malignancies occurred in ei- ther group.

Discussion

Locatelli et al. argued that most long-term side effects in pediatric patients who have received HSCT are associated with the conditioning regimen performed before trans- plantation, including radiotherapy-induced toxicity [15]. In their study, growth impairment was observed in most pa- tients in the TBI group, and 30-40% of these patients pre-

sented thyroid function abnormalities. In addition, delayed puberty development was observed in some patients in the TBI group. According to Sanders et al., the rates of thyroid function abnormalities and growth hormone deficiency were associated more strongly with a TBI-based condition- ing regimen than they were with a non-TBI-based con- ditioning regimen among pediatric patients who had under- gone HSCT [16]. Moreover, demand for synthetic growth hormone therapy in the TBI-based conditioning group was higher than that in the non-TBI-based conditioning group.

Park et al. conducted a single institution study consisting

of 28 pediatric patients with acute leukemia in order to de-

termine the effect of TBI-based conditioning [17]. The most common chronic complication associated with TBI was short stature, which occurred at a rate of 14.3%. On the basis of height measurements before and after HSCT, Shankar et al. reported that the use of busulfan and cyclo- phosphamide as a non-TBI-based conditioning regimen had no effect on the growth of pediatric patients [18].

In the present study, five out of the seven total patients in the TBI-based conditioning group were documented as long-term survivors. Three among those five patients were found to have short stature (＜3 percentile), and these pa- tients showed no response to growth hormone therapy.

However, short stature was not observed in the non-TBI- based conditioning group. Thus, TBI had a negative effect on pediatric patients by causing late sequelae, including growth impairment. Therefore, the potential negative ef- fects of TBI-based conditioning regimens must be carefully considered when selecting a conditioning regimen.

Several studies initiated in the 1970s aimed to develop suitable TBI alternative such as a chemotherapy-based con- ditioning regimen. After Santos et al. first confirmed the myeloablative effect of busulfan in a murine aplastic anemia model [19], a busulfan＋cyclophosphamide regimen became the most frequently used alternative to a TBI-based regimen.

Busulfan has high myeloablative and anti-leukemic activ- ities but a weak immunosuppressive effect, which can be augmented by simultaneous use of cyclophosphamide [20].

A busulfan＋cyclophosphamide conditioning regimen was first used in pediatric HSCT in the 1980s. Busulfan is espe- cially suitable for a pediatric conditioning regimen because its plasma clearance rate is 4- to 5-fold higher in children than in adults, resulting in lower toxicity [21].

Despite these advantages of busulfan, previous studies have reported that the survival rate of pediatric patients with ALL after transplantation was lower with a busul- fan-based conditioning regimen than with a TBI-based con- ditioning regimen. Ringden et al. conducted a study on 167 patients with leukemia who underwent HSCT using hema- topoietic stem cells obtained from HLA-identical donors [22].

The study subjects were randomized into a busulfan-based conditioning group or TBI-based conditioning group for comparison of post-transplantation results. The 3-year sur-

vival rate in the TBI group (76%) was significantly higher than that in the busulfan group (62%). The transplantation-related mortality rate in the busulfan group (62%) was significantly higher than that in the TBI group (12%). The results of this study established TBI as the treatment of choice. However, this study included pediatric as well as adult patients, and patients with acute and chronic myeloid leukemia in addi- tion to patients with acute lymphoblastic leukemia. In a study by Granados et al., 156 patients with ALL were div- ided into TBI-based and non-TBI-based conditioning groups for comparison of EFS, transplant-related mortality, and probability of relapse between groups [23]. The 6-year EFS rate after transplantation in the TBI group (43%) was sig- nificantly higher than that in the non-TBI group (22%).

Transplant-related mortality did not differ between the groups. However, the probability of relapse at 3 years after transplantation in the non-TBI group (71%) was sig- nificantly higher than that in the TBI group (47%). These results, established the TBI-based conditioning regimen as the standard preparative regimen for patients with ALL.

Although this study included only patients with ALL, it in- cluded both pediatric and adult patients. Kim et al. com- pared HSCT outcomes in 77 patients with various pediatric leukemias divided into a TBI group and a non-TBI group, and reported no difference in the overall 5-year EFS be- tween the two groups [24]. However, when data from only patients with ALL were compared between groups, the 5-year EFS rate in the TBI group (65%) was significantly higher than that in the non-TBI group (17%). Davies et al.

compared outcomes between 451 ALL patients treated with TBI＋cyclophosphamide and 176 patients treated with bu- sulfan＋cyclophosphamide; all patients were aged ＜20 years. [11] The 3-year OS rate in the TBI group (55%) was significantly higher than that in the non-TBI group (40%).

The 3-year EFS rate in the TBI group was also significantly higher than that in the non-TBI group. In a randomized prospective study conducted by Bunin et al., outcomes were compared among 43 patients with ALL aged ＜21 years who were randomized into a TBI group and a non-TBI group [25]. The 3-year EFS rate in the TBI group (58%) was significantly higher than that in the non-TBI group (29%).

Taken together, the results of all these aforementioned

studies indicate that a TBI-based conditioning regimen is superior to a non-TBI-based conditioning regimen in terms of survival rate, despite the potential for development of late sequelae. The poor outcomes of busulfan-based con- ditioning regimens might be because the plasma clearance rate of busulfan in pediatric patients is higher than that in adults, resulting in lower therapeutic drug levels of bu- sulfan in pediatric patients. However, this higher clearance rate might also result in lower toxicity in pediatric patients, despite the disadvantage of poor survival and a high re- lapse rate [21].

In the present study, the 5-year EFS rate in the TBI group was not significantly different from that in the non-TBI group. Thus, in contrast to the aforementioned studies, the present study revealed that outcomes in the non-TBI group were not inferior to those in the TBI group, suggesting that a non-TBI-based conditioning regimen can be developed and used as a viable alternative to a TBI-based conditioning regimen. In addition, no endocrine complications were ob- served in the non-TBI group, suggesting that a non-TBI- based conditioning regimen might result in a better quality of life in pediatric patients with ALL who are long-term sur- vivors after transplantation. The discrepancy in results be- tween the present study and previous studies might be a result of the differences in populations between these stud- ies i.e. adult vs. pediatric populations and patients with ALL vs. patients with other leukemias.

This study has some limitations. First, it was a single-cen- tered, retrospective study with a relatively small number of subjects. Second, combined chemotherapy with TBI and busulfan in the TBI group and non-TBI group was not the same for each patient. Third, the different donor sources and high number of CR1 patients in the non-TBI group could affect survival outcomes. In addition, a trend of de- creased EFS was observed in the non-TBI group. This ob- servation should be interpreted with caution considering the small sample size of the study. Furthermore, T-cell lym- phoblastic leukemia and infant ALL, which are not relevant to transplant indication, were subjects for transplantation at CR1. This might also have an effect on the result and it will be the limits of retrospective study.

In summary, the TBI-based regimen is still a standard

preparative regimen for HSCT of pediatric acute lympho- blastic leukemia. However, considering that long-term com- plications of pediatric patients and the adverse effects of the TBI-based regimen affect the quality of life, the non-TBI-based conditioning regimen will be an alternative treatment option of the treatment of pediatric acute lym- phoblastic leukemia, avoiding the adverse effects of the TBI-based regimens. 

Acknowledgments

This work was supported by the 2015 Yeungnam Univer- sity Research Grant.

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